The present invention is directed to processes for the preparation of 5-fluoro-6-chlorooxindole (III). 5-Fluoro-6-chlorooxindole is particularly useful as an intermediate in the synthesis of certain analgesic and antiinflammatory agents having the formula ##STR2## wherein R.sup.1 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]-hept-5-en-2-yl and --(CH.sub.2).sub.n --Q--R; wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is selected from the group consisting of fluoro, chloro, bromo, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons and trifluoromethyl; n is zero, 1 or 2; Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]thiophene; and R is hydrogen or alkyl having 1 to 3 carbons.
The compounds of the formula (A), their preparation and their utility as an analgesic and antiinflammatory agents are fully described herein and in U.S. Pat. No. 4,556,672.
5-Fluoro-6-chlorooxindole has been previously prepared by Kadin, U.S. Pat. No. 4,556,672, via 3-chloro-4-fluoroaniline which was reacted with chloroacetyl chloride to produce N-(2-chloroacetyl)-3-chloro-4-fluoroaniline, which in turn was cyclized in the presence of a strong alkali metal halide (Lewis Acid, e.g., aluminum chloride) to produce 5-fluoro-6-chlorooxindole.
Similar types of reactions, as illustrated in Scheme 2, using hydrogen fluoride-pyridine to rearrange an aromatic hydroxylamine is well-documented in the literature: Fidler et al., J. Org. Chem., 26, 4014 (1961), Patrick al. J. Org. Chem., 39, 1758 (1974). Incorporating a nitrile in the reaction to obtain the desired compound (III) from (IV) is novel and not anticipated by the literature. The desired compound (III) is not obtained, in the absence of an alkyl or aryl nitrile, when (IV) is reacted with hydrogen fluoride-pyridine or anhydrous hydrogen fluoride alone.
This invention also relates to the novel compounds (I) and (II) having the formulas ##STR3## which are intermediates formed in the process of this invention and which therefore are useful for the production of the compound with formula (III).